Orally dosed pharmaceutical compositions comprising a delivery agent in micronized form

ABSTRACT

Solid pharmaceutical compositions and methods of their use suitable for the oral delivery of pharmacologically active agents, e.g. peptides, comprising a therapeutically-effective amount of a pharmacologically active agent; a crospovidone or povidone; and a delivery agent for said pharmacologically active agent are disclosed. The compositions utilize micronized forms of the delivery agent which provides enhanced bioavailability of pharmacologically active agents, particularly calcitonin.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to oral compositions for the delivery ofpharmacologically active agents, to methods of enhancing thebioavailability of orally administered pharmacologically active agents,and to methods of treating and/or preventing disease in mammals,particularly humans, by orally administering a pharmacologically activeagent in accordance with the invention.

2. Description of the Related Art

Oral delivery of pharmacologically active agents is generally thedelivery route of choice since it is convenient, relatively easy andgenerally painless, resulting in greater patient compliance relative toother modes of delivery. However, biological, chemical and physicalbarriers such as varying pH in the gastrointestinal tract, powerfuldigestive enzymes, and active agent impermeable gastrointestinalmembranes, makes oral delivery of some pharmacologically active agentsto mammals problematic, e.g. the oral delivery of calcitonins, which arelong-chain polypeptide hormones secreted by the parafollicular cells ofthe thyroid gland in mammals and by the ultimobranchial gland of birdsand fish, has proven difficult due, at least in part, to theinsufficient stability of calcitonin in the gastrointestinal tract aswell as the inability of calcitonin to be readily transported throughthe intestinal walls into the blood stream.

U.S. Pat. Nos. 5,773,647 and 5,866,536 describe compositions for theoral delivery of active agents, such as heparin and calcitonin, withmodified amino acids, such as, N-(5-chlorosalicyloyl)-8-aminocaprylicacid (5-CNAC), N-(10-[2-hydroxybenzoyl]aminodecanoic acid (SNAD), andN-(8-[2-hydroxybenzoyl]amino)caprylic acid (SNAC) In addition, WO00/059863 discloses the disodium salts of formula I

wherein

-   -   R¹, R², R³, and R⁴ are independently hydrogen, —OH, —NR⁶R⁷,        halogen, C₁-C₄alkyl, or C₁-C₄alkoxy;    -   R⁵ is a substituted or unsubstituted C₂-C₁₆alkylene, substituted        or unsubstituted C₂-C₁₆alkenylene, substituted or unsubstituted        C₁-C₁₂alkyl(arylene), or substituted or unsubstituted        aryl(C₁-C₁₂alkylene); and    -   R⁶ and R⁷ are independently hydrogen, oxygen, or C₁-C₄ alkyl;        and hydrates and solvates thereof as particularly efficacious        for the oral delivery of active agents, such as calcitonin,        cyclosporin and heparin.

The present invention describes pharmaceutical compositions whichprovide still greater oral bioavailability of pharmacologically activeagents, e.g. peptides such as calcitonin.

SUMMARY OF THE INVENTION

Accordingly, the present invention is directed to pharmaceuticalcompositions which, quite surprisingly, greatly enhance the oralbioavailability of active agents, particularly peptides. Specifically,the invention provides solid pharmaceutical compositions suitable forthe oral delivery of pharmacologically active agents, comprising

-   -   1. a therapeutically-effective amount of a pharmacologically        active agent;    -   2. pharmaceutically acceptable inactive excipients; and    -   3. a delivery agent for said pharmacologically active agent,        wherein said delivery agent is in micronized form.

In another embodiment the present invention provides solidpharmaceutical compositions suitable for the oral delivery ofcalcitonin, comprising

-   -   1. a therapeutically-effective amount of a calcitonin; and    -   2. pharmaceutically acceptable inactive excipients, and    -   3. a delivery agent for said calcitonin, wherein said delivery        agent is in micronized form.

In an additional embodiment of the present invention thepharmaceutically acceptable inactive excipient may be either or both ofthe polymers crospovidone or povidone.

In a still further embodiment of the present invention the solidpharmaceutical composition suitable for oral delivery may also comprisea diluent.

In addition in another embodiment of the present invention the solidpharmaceutical composition suitable for oral delivery may also comprisea lubricant.

In a further embodiment, the invention is directed to a method forenhancing the oral bioavailability of a pharmacologically active agent,said method comprising administering to a subject in need of saidpharmacologically active agent an effective amount of a pharmaceuticalcomposition according to the instant invention.

In a still further embodiment, the invention is directed to a method oftreatment of bone related diseases and calcium disorders comprisingadministering to a patient in need of such treatment a therapeuticallyeffective amount of a composition according to the instant invention,wherein said pharmacologically active agent is calcitonin.

Further features and advantages of the invention will become apparentfrom the following detailed description of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The pharmacologically active agents suitable for use in the instantinvention include both therapeutic as well as preventative agents and isdirected particularly to agents which by themselves do not pass or whichpass only a small amount of the administered dose through thegastrointestinal mucosa and/or are susceptible to cleavage by acids andenzymes in the gastro-intestinal tract. The pharmacologically activeagents include, but are not limited to proteins; polypeptides; hormones;polysaccharides including mixtures of muco-polysaccharides;carbohydrates; lipids; and combinations thereof.

Specific examples of pharmacologically active agents include, but arenot limited to, the following, including synthetic, natural orrecombinant sources thereof: growth hormone, including human growthhormones (hGH), recombinant human growth hormones (rhGH), bovine growthhormones, and porcine growth hormones; growth hormone-releasinghormones; interferons, including α, β, and γ-interferon; interleukin-1;interleukin-2; insulin, including porcine, bovine, human, and humanrecombinant, optionally having counter ions including sodium, zinc,calcium and ammonium; insulin-like growth factor, including IGF-1;heparin, including unfractionated heparin, heparinoids, dermatans,chondroitins, low, very low and ultra low molecular weight heparins;calcitonin, including salmon, porcine, eel, chicken and human;erythopoietein; atrial naturetic factor; antigens; monoclonalantibodies; somatostatin; protease inhibitors; adrenocorticotropin,gonadotropin releasing hormone; oxytocin; leutinizing-hormone-releasinghormone; follicle stimulating hormone; glucocerebrosidase;thrombopoietin; filgrastim; prostaglandins; cyclosporin; vasopressin;cromolyn sodium (sodium or disodium chromoglycate); vancomycin;desferrioxamine (DFO); parathyroid hormone (PTH), including itsfragments; antimicrobials, including anti-fungal agents; vitamins;analogs, fragments, mimetics or polyethylene glycol (PEG)-modifiedderivatives of these compounds; or any combination thereof.

An interesting pharmacologically active agent is a pharmacologicallyactive peptide, particularly bone active agents, and even moreparticularly calcitonin.

Bone active agents include classes of agents which display in vivopharmacological activity in animals such as stabilization, healing, orgrowth of bone, deceleration or inhibition of bone turnover,deceleration or inhibition of bone resorption, inhibition of osteoclastactivity, and stimulation of osteoblast activity. Some of these agentsmay be peptidic, for example calcitonins, parathyroid hormone (PTH), PTHfragments, analogs and releasers, and Transforming Growth Factors (TGFs)fragments, analogs and releasers. The bone active agents may also besmall molecule non-peptidic structures which show in vivopharmacological bone activities as described above in this paragraph.

A known class of such pharmacologically active agents, calcitonins, havevarying pharmaceutical utility and are commonly employed in thetreatment of e.g. Paget's disease, hypercalcemia and postmenopausalosteoporosis. Various calcitonins, including salmon, pig and eelcalcitonin are commercially available and commonly employed for thetreatment of e.g. Paget's disease, hypercalcemia of malignancy andosteoporosis. The calcitonin can be any calcitonin, including natural,synthetic or recombinant sources thereof, as well as calcitoninderivatives such as 1,7-Asu-eel calcitonin. The compositions cancomprise a single calcitonin or any combination of two or morecalcitonins. The preferred calcitonin is synthetic salmon calcitonin.

The calcitonins are commercially available or may be synthesized byknown methods.

The amount of pharmacologically active agent is generally an amounteffective to accomplish the intended purpose, e.g. a therapeuticallyeffective amount. However, the amount can be less than that amount whena plurality of the compositions are to be administered, i.e., the totaleffective amount can be administered in cumulative dosage units. Theamount of active agent can also be more than the effective amount whenthe composition provides sustained release of the pharmacologicallyactive agent. The total amount of active agent to be used can bedetermined by methods known to those skilled in the art. However,because the compositions may deliver the active agent more efficientlythan prior compositions, less amounts of active agent than those used inprior dosage unit forms or delivery systems can be administered to asubject while still achieving the same blood levels and/or therapeuticeffects.

When the pharmacologically active agent is salmon calcitonin, theappropriate dosage will, of course, vary depending upon, for example,the host and the nature and severity of the condition being treated.However, in general, satisfactory results will be obtained systemicallyat daily dosages of from about 0.5 μg/kg to about 10 μg/kg animal bodyweight, preferably 1 μg/kg to about 6 μg/kg body weight.

The pharmacologically active agent generally comprises from 0.05 to 70percent by weight relative to the total weight of the overallpharmaceutical composition, preferably an amount of from 0.01 to 50percent by weight, more preferably 0.3 to 30 percent by weight relativeto the total weight of the overall pharmaceutical composition.

The pharmaceutically acceptable inactive excipients may include polymersand inactive compounds which for example, aid the formulation ormanufacturing of the solid oral dosage form contemplated by the presentinvention or which may aid the release of the solid oral composition inthe gastrointestinal environment.

The pharmaceutically inactive ingredients, referred to above, forexample optionally include crospovidones and povidones, which may be anycrospovidone and povidone. Crospovidone is a synthetic crosslinkedhomopolymer of N-vinyl-2-pyrrolidone, also called1-ethenyl-2-pyrrolidinone, having a molecular weight of 1,000,000 ormore. Commercially available crospovidones include Polyplasdone XL,Polyplasdone XL-10, Polyplasdone INF-10 available from ISP, Kollidon CL,available from BASF Corporation. The preferred crospovidone isPolyplasdone XL.

Povidone is a synthetic polymer consisting of linear1-vinyl-2-pyrrolidinone groups having a molecular weight generallybetween 2,500 and 3,000,000. Commercially available povidones includeKollidon K-30, Kollidon K-90F available from BASF Corporation andPlasdone K-30 and Plasdone K-29/32, available from ISP.

As mentioned above, the crospovidones and povidones are commerciallyavailable. Alternatively, they may be synthesized by known processes.

The crospovidone, povidone or combination thereof is generally presentin the compositions in an amount of from 0.5 to 50 percent by weightrelative to the total weight of the overall pharmaceutical composition,preferably an amount of from 2 to 25 percent, more preferably 5 to 20percent by weight relative to the total weight of the pharmaceuticalcomposition.

The delivery agents useful in the present invention are any agentsuseful for delivering the particular pharmacologically active agent.Suitable delivery agents are any one of the 123 modified amino acidsdisclosed in aforementioned U.S. Pat. No. 5,866,536 or any one of the193 modified amino acids described in the aforementioned U.S. Pat. No.5,773,647 or any combination thereof. The contents of the aforementionedU.S. Pat. Nos. 5,773,647 and 5,866,536 are hereby incorporated byreference in their entirety. In addition, the delivery agent can be thedisodium salt of any of the aforementioned modified amino acids as wellas ethanol solvates and hydrates thereof. Suitable compounds includecompounds of the following formula I

wherein

R¹, R², R³, and R⁴ are independently hydrogen, —OH, —NR⁶R⁷, halogen,C₁-C₄alkyl, or C₁-C₄alkoxy;

R⁵ is a substituted or unsubstituted C₂-C₁₆alkylene, substituted orunsubstituted C₂-C₁₆alkenylene, substituted or unsubstitutedC₁-C₁₂alkyl(arylene), or substituted or unsubstitutedaryl(C₁-C₁₂alkylene); and

R⁶ and R⁷ are independently hydrogen, oxygen, or C₁-C₄ alkyl; andhydrates and alcohol solvates thereof. The compounds of formula I aswell as their disodium salts and alcohol solvates and hydrates thereofare described in WO 00/059863, along with methods for preparing them.

The disodium salt may be prepared from the ethanol solvate byevaporating or drying the ethanol solvate by methods known in the art toform the anhydrous disodium salt. Drying is generally carried out at atemperature of from about 80 to about 120° C., preferably from about 85to about 90° C., and most preferably at about 85° C. The drying step isgenerally performed at a pressure of 26″ Hg or greater. The anhydrousdisodium salt generally contains less than about 5% by weight of ethanoland preferably less than about 2% by weight of ethanol, based on 100%total weight of anhydrous disodium salt.

The disodium salt of the delivery agent can also be prepared by making aslurry of the delivery agent in water and adding two molar equivalentsof aqueous sodium hydroxide, sodium alkoxide or the like. Suitablesodium alkoxides include, but are not limited to, sodium methoxide,sodium ethoxide, and combinations thereof.

A still further method of preparing the disodium salt is by reacting thedelivery agent with one molar equivalent of sodium hydroxide to yieldthe disodium salt.

The disodium salt can be isolated as a solid by concentrating thesolution containing the disodium salt to a thick paste by vacuumdistillation. This paste may be dried in a vacuum oven to obtain thedisodium salt of the delivery agent as a solid. The solid can also beisolated by spray drying an aqueous solution of the disodium salt.

The delivery agents may be prepared by methods known in the art, e.g.,as mentioned above, by methods described in U.S. Pat. Nos. 5,773,647 and5,866,536.

The ethanol solvates, as described in the aforementioned WO 00/059863,include, but are not limited to, a molecular or ionic complex ofmolecules or ions of ethanol solvent with molecules or ions of thedisodium salt of the delivery agent. Typically, the ethanol solvatecontains about one ethanol molecule or ion for every molecule ofdisodium salt of the delivery agent.

The ethanol solvate of the disodium salt of the delivery agent can beprepared by dissolving the delivery agent in ethanol. Typically, eachgram of delivery agent is dissolved in from about 1 to about 50 mL ofethanol and generally, from about 2 to about 10 mL of ethanol. Thedelivery agent/ethanol solution is then reacted with a molar excess of asodium containing salt, such as a monosodium containing salt, relativeto delivery agent, i.e. for every mole of delivery agent there is morethan one mole of sodium cations, yielding the ethanol solvate. Suitablemonosodium salts include, but are not limited to, sodium hydroxide;sodium alkoxides, such as sodium methoxide and sodium ethoxide; and anycombination of the foregoing. Preferably, at least about two molarequivalents of the monosodium containing salt are added to the ethanolsolution, i.e. for every mole of delivery agent there is at least abouttwo moles of sodium cations. Generally, the reaction is performed at orbelow the reflux temperature of the mixture, such as at ambienttemperature. The ethanol solvate is then recovered by methods known isthe art, such as, concentration of the resulting slurry at atmosphericdistillation, cooling the concentrated slurry and filtering the solid.The recovered solid can then be vacuum dried to obtain the ethanolsolvate.

The hydrates of the disodium salts of the delivery agents may beprepared by drying the ethanol solvate to from an anhydrous disodiumsalt, as described above, and hydrating the anhydrous disodium salt.Preferably, the monohydrate of the disodium salt is formed. Since theanhydrous disodium salt is very hydroscopic, the hydrate forms uponexposure to atmospheric moisture. Generally, the hydrating step isperformed at from about ambient temperature to about 50° C., preferablyambient temperature to about 30° C. and in an environment having atleast 50% relative humidity. Alternatively, the anhydrous disodium saltmay be hydrated with steam.

The preferred delivery agents are N-(5-chlorosalicyloyl)-8-aminocaprylicacid (5-CNAC), N-(10-[2-hydroxybenzoyl]amino)decanoic acid (SNAD),N-(8-[2-hydroxybenzoyl]amino)caprylic acid (SNAC)and their monosodiumand disodium salts, ethanol solvates of their sodium salts and themonohydrates of their sodium salts and any combinations thereof. Themost preferred delivery agent is the disodium salt of 5-CNAC and themonohydrate thereof.

The delivery agent, 5 CNAC, SNAD, and SNAC are very water soluble andnearly fully, i.e. greater than 90%, absorbed by the gastrointestinaltract whether it is ingested in micronized or coarse form. However, ithas been found, surprisingly, that when a micronized form of one ofthese carrier agents is employed in the composition, the absorption ofthe pharmacologically active agent of the present composition is morecompletely absorbed into the blood stream. Therefore, the use ofmicronized carrier agent is a required element of the present invention.

A micronized form of the carrier agent, which is utilized in preparationof the solid oral dosage form of the present invention, is defined as acarrier agent which, when added to the present composition mixture ofpharmacologically active agent and pharmaceutically inactiveingredients, has an average particle size of less than 40 micrometers.Desirably the carrier agent of the present invention has a micronizedform which is defined as an average particle size of less than 20microns. More interestingly, the carrier agent for the present inventionhas a micronized form which is defined as an average particle size ofless than 10 microns.

Micronized forms of the carrier agent of the present invention may beprepared by grinding it in a grinding mill which is acceptable forgrinding pharmaceutical ingredients and which is capable of grinding thepharmaceutical ingredients and/or carrier agent to a fine and uniformmicronized particle size. An example of such a grinding mill is an AirJet Mill Gem T® (Copley Scientific, Ltd., Nottingham, UK). The finelyground carrier agent either separately or finely ground carrier agentplus any combination of finely ground additional ingredients of thepresent invention may then be screened, for example, over a mesh screenhaving the appropriate openings, in order to allow only thoseingredients which have the required particle size to pass through and becollected for use in the present invention.

The pharmaceutical compositions of the present invention typicallycontain a delivery effective amount of one or more of the deliveryagents, i.e. an amount sufficient to deliver the active agent for thedesired effect. Generally, the delivery agent is present in an amount of2.5% to 99.4% by weight, more preferably 25% to 50% by weight.

The pharmaceutical compositions of the present invention may be providedas a capsule including a soft-gel capsule, tablet, caplet or other solidoral dosage form, all of which can be prepared by methods well known inthe art.

The compositions may additionally comprise additives in amountscustomarily employed including, but not limited to, a pH adjuster, apreservative, a flavorant, a taste-masking agent, a fragrance, ahumectant, a tonicifier, a colorant, a surfactant, a plasticizer, alubricant such as magnesium stearate, a flow aid, a compression aid, asolubilizer, an excipient, a diluent such as microcrystalline cellulose,e.g. Avicel PH 102® (supplied by FMC corporation 1735 Market StreetPhiladelphia, Pa. 19103, USA), or any combination thereof. Otheradditives may include phosphate buffer salts, citric acid, glycols, andother dispersing agents.

The composition may also include one or more enzyme inhibitors, such asactinonin or epiactinonin and derivatives thereof; aprotinin, Trasyloland Bowman-Birk inhibitor.

Further, a transport inhibitor, i.e. a ρ-glycoprotein such asKetoprofin, may be present in the compositions of the present invention.

Preferably, the solid pharmaceutical compositions of the instantinvention include a diluent, such as Avicel®, and a lubricant, such asmagnesium stearate.

The solid pharmaceutical compositions of the instant invention can beprepared by first grinding either the carrier agent or the carrier agentwith any combination of the additional ingredients of the presentcomposition to a micronized particle size. The micronized carrier agentor micronized carrier agent plus micronized additional ingredients ofthe present invention may then be further processed by conventionalmethods e.g. by blending a mixture of the active agent or active agents,the delivery agent, the crospovidone or povidone and other ingredients,kneading, and filling into capsules or, instead of filling intocapsules, molding followed by further tableting or compression-moldingto give tablets. In addition, a solid dispersion may be formed by knownmethods followed by further processing to form a tablet or capsule.

Preferably, the ingredients in the pharmaceutical compositions of theinstant invention are homogeneously or uniformly mixed throughout thesolid dosage form.

The compositions of the present invention may be administered to deliveran active agent to any animal in need thereof, including, but notlimited to, mammals, such as rodents, cows, pigs, dogs, cats, andprimates, particularly humans.

The following examples serve to further illustrate the invention andwill be readily understood by one of ordinary skill in the art. Theexamples are not meant to be limiting of the present invention in anyway.

EXAMPLE 1

Micronized 5-CNAC and tablets of salmon calcitonin plus micronized5-CNAC may be prepared in accordance with the present invention asfollows:

Preparation of Micronized 5-CNAC

Coarse 5-CNAC, which is to be micronized, is added to a jet mill (AirJet Mill Gem T® Copley Scientific, Ltd., Nottingham, UK) using a 80ceramic pan cake jet mill, 8 cm diameter, 6 bar N2, 0.5 mm nozzles withmanual feed of about 700 g/h. The coarse 5-CNAC is jet milled andperiodically sampled under microscope with reference ruler measurementsto identify when the average desired micronized particle size isobtained. Three different batches are ground to create 6 um, 35 um, and46 um batches. Individual sieving of the separate micronized batches isthen done by using a conical sieve mill (Quadro Comil, QuadroEngineering Incorporated 613 Colby Drive, Waterloo, Ontario, Canada N2V1A1) with a U10, 813 um conical sieve, round beater, operating at 1500upm with throughput of about 150 kg/h. Formulation I. Salmon CalcitoninFormulation with 5-CNAC of Different Particle Size Ingredient Amount(mg) Percent (%) Salmon Calcitonin 1 0.25 Micronized 5-CNAC 228 57Avicel PH 102 ® 147 36.75 Crospovidone, NF 20 5 Magnesium stearate 4 1Total 400 100

Preparation of Formulation 1

Three different batches of tablets are prepared using the threedifferent batches of micronized 5-CNAC disodium, one tablet batch havingan average 5-CNAC disodium particle size of 46 microns (Batch A), asecond tablet batch having an average 5-CNAC disodium particle size of 6microns (Batch B), and a third tablet batch having an average 5-CNACdisodium particle size of 35 microns (Batch C).

0.50 g of salmon calcitonin, pre-screened through a 40 mesh screen, 57.g of micronized 5-CNAC disodium salt, screened through a 35 mesh screen,and 10 g of Polyplasdone XL (crospovidone, NF, International SpecialtyProducts, 1361 Alps Road, Wayne, N.J., 07470, USA) is combined in a 500mL jar and is mixed using a Turbula mixer for 100 revolutions at a speedof 46 RPM. An additional 57. g of micronized 5-CNAC disodium salt,screened through a 35 mesh screen, and 36.75 g of Avicel PH 102 ® isadded to the jar and mixed for 500 revolutions at a speed of 46 RPM. Afurther 36.75 g of Avicel PH 102 ® is added to the jar and is mixed foran additional 100 revolutions at a speed of 46 RPM. 4.0 g of magnesiumstearate is screened into the jar using a 35 mesh screen and is blendedfor 1 minute at a speed of 46 RPM. The final blend is compressed intotablets using a Manesty B3B tablet press. The tablet weight isapproximately 400 mg.

The bioavailability of the tablets created in Example 1 may be tested asfollows:

EXAMPLE 2 Primate Administration

The tablets are prepared as in Example 1 using three different batchesof micronized 5-CNAC disodium, one tablet batch having an average 5-CNACdisodium particle size of 46 microns (Batch A), a second tablet batchhaving an average 5-CNAC disodium particle size of 6 microns (Batch B),and a third tablet batch having an average 5-CNAC disodium particle sizeof 35 microns (Batch C). The tablets prepared from each of the threedifferent batches are administered to the same four Rhesus monkeysseparately on different days as follows:

The Rhesus monkeys fast overnight prior to dosing and are restrained inchairs fully conscious, for the duration of the study period. One tabletfrom Batch A or Batch B or Batch C is administered to each monkey via agavage tube followed by 10 mL of water.

Rhesus monkey blood samples are collected immediately beforeadministration and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, and 6 hoursafter administration. A tablet from each of the remaining two tabletbatches is dosed and blood samples are collected in a similar manner buton a separate day for each of the remaining tablet batches. Resultingplasma salmon calcitonin for each dose and for each monkey is determinedby radioimmunoassay. For each monkey, the primate plasma salmoncalcitonin (SCt) for one batch and one time period, mean plasma SCtconcentrations for all monkeys for one batch and one time period,Standard Deviation (SD) of plasma SCt concentrations for one batch andone time period, and Standard Error of the Mean (SEM) for plasma SCtconcentrations for all monkeys for one batch and one time period arecalculated and reported in Tables 1, 2, and 3 as follows. TABLE 1 BATCHA: AVERAGE 5-CNAC PARTICLE SIZE 46 MICROMETERS Salmon Calcitonin (SCt)Plasma Concentrations [pg/mL] (Single Oral Tablet (200 mg 5-CNAC + 1 mgSCt) to the Rhesus Monkey) Animal Time [hours] no. 0 0.25 0.50 0.75 11.5 2 3 4 5 6 1 0.0 17.8 91.7 279.7 449.2 278.8 48.0 10.5 5.3 3.3 0.0 20.0 117.4 535.0 430.8 981.4 1718.0 2396.4 719.5 253.6 102.1 62.9 3 0.0113.9 754.5 1502.0 2351.0 2066.0 2684.4 1310.0 649.6 280.6 156.5 4 0.046.0 127.0 425.5 765.8 1102.0 1599.0 1022.0 419.3 87.0 23.4 Mean 0.073.8 377.1 659.5 1136.9 1291.2 1682.0 765.5 332.0 118.3 60.7 SD 0.0 49.7322.2 566.0 838.4 783.8 1182.1 558.1 271.6 116.6 68.9 SEM 0.0 24.9 161.1283.0 419.2 391.9 591.0 279.0 135.8 58.3 34.5Lower Limit of Quantification (LLOQ) = 2.5 pg/mL, concentrations belowLLOQ were set to zero for Table 1

TABLE 2 BATCH B: AVERAGE 5-CNAC PARTICLE SIZE 6 MICROMETERS SalmonCalcitonin (SCt) Plasma Concentrations [pg/mL] (Single Oral Tablet (200mg 5-CNAC + 1 mg SCt) to the Rhesus Monkey) Animal Time [hours] no. 00.25 0.50 0.75 1 1.5 2 3 4 5 6 1 0.0 265.6 315.8 245.6 357.2 1927.03010.0 863.2 139.4 48.5 20.8 2 0.0 607.0 777.0 1336.0 1602.0 4146.07521.0 2681.0 420.8 73.9 43.2 3 0.0 80.9 225.5 325.6 655.6 1478.0 3979.02775.0 520.2 91.5 41.3 4 0.0 286.4 155.3 237.7 241.0 269.7 294.2 321.0179.8 67.5 13.6 Mean 0.0 310.0 368.4 536.2 714.0 1955.2 3701.1 1660.1315.1 70.4 29.7 SD 0.0 218.5 280.2 534.7 617.2 1619.6 2986.3 1253.5184.8 17.8 14.8 SEM 0.0 109.2 140.1 267.3 308.6 809.8 1493.1 626.7 92.48.9 7.4Lower Limit of Quantification (LLOQ) = 2.5 pg/mL, concentrations belowLLOQ were set to zero for Table 2

TABLE 3 BATCH C: AVERAGE 5-CNAC PARTICLE SIZE 35 MICROMETERS SalmonCalcitonin (SCt) Plasma Concentrations [pg/mL] (Single Oral Tablet (200mg 5-CNAC + 1 mg SCt) to the Rhesus Monkey) Animal Time [hours] no. 00.25 0.50 0.75 1 1.5 2 3 4 5 6 1 0.0 36.1 94.7 428.0 739.4 2568.0 4025.01348.0 499.6 218.4 98.1 2 0.0 10.9 55.0 168.9 248.2 507.3 654.0 434.8177.3 68.8 38.9 3 0.0 172.3 336.6 409.5 584.9 1487.0 2087.0 1479.0 162.052.0 17.2 4 0.0 7.9 46.9 208.1 390.1 1237.0 2347.0 1342.0 192.3 42.319.2 Mean 0.0 56.8 133.3 303.6 490.7 1449.8 2278.3 1151.0 257.8 95.443.4 SD 0.0 78.0 137.1 134.1 215.8 853.5 1382.1 481.6 161.7 82.7 37.8SEM 0.0 39.0 68.6 67.1 107.9 426.7 691.1 240.8 80.8 41.4 18.9Lower Limit of Quantification (LLOQ) = 2.5 pg/mL, concentrations belowLLOQ were set to zero for Table 3

The foregoing clearly shows that the compositions according to theinstant invention allow considerably improved oral bioavailability ofactive agent. The improved bioavailability results in high in vivoconcentrations of active agent, particularly calcitonin, being achievedvia oral delivery, and in correlation to the particle sizes of 5-CNAC inthe oral formulations of the Examples.

The foregoing embodiments and examples are given merely to illustratethe instant invention and are not intended to be limiting. Numerousother embodiments and variations are within the scope of the inventionand readily accessible to those skilled in the art.

1. A solid pharmaceutical composition suitable for the oral delivery ofa pharmacologically active agent comprising a. atherapeutically-effective amount of a pharmacologically active agent; b.pharmaceutically acceptable inactive excipients, and c. a delivery agentfor said pharmacologically active agent, wherein said delivery agent isin micronized form.
 2. A composition according to claim 1 wherein theactive agent is a peptide.
 3. A composition according to claim 2 whereinthe peptide is a calcitonin.
 4. A composition according to claim 3wherein the calcitonin is salmon calcitonin.
 5. A composition accordingto claim 1 wherein said inactive excipients are selected from the groupconsisting of crospovidone and povidone.
 6. A composition according toclaim 1 wherein the delivery agent is selected from the group consistingof 5-CNAC, SNAD, and SNAC.
 7. A composition according to claim 1 whereinthe delivery agent is selected from the group consisting of a disodiumsalt of 5-CNAC, a disodium salt of SNAD, and a disodium salt of SNAC. 8.A composition according to claim 1 which additionally includes adiluent.
 9. A composition according to claim 8 wherein the diluent ismicrocrystalline cellulose.
 10. A composition according to claim 1 whichadditionally includes a lubricant.
 11. A composition according to claim10 wherein the lubricant is magnesium stearate.
 12. A method forenhancing the oral bioavailability of a pharmacologically active agent,said method comprising administering to a patient in need of apharmacologically active agent, an effective amount of a pharmaceuticalcomposition according to claim
 1. 13. A method of treatment of bonerelated diseases and calcium disorders comprising administering to apatient in need of such treatment a therapeutically effective amount ofa composition according to claim 1, wherein said pharmacologicallyactive agent is a bone active agent.
 14. A method according to claim 13,wherein said pharmacologically active agent is calcitonin.
 15. A methodaccording to claim 14 wherein said calcitonin is salmon calcitonin. 16.(canceled)